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Acute Leukemias

Impairment of Na+,K+-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide

Leukemia volume 21, pages 1669–1678 (2007)Cite this article

A Corrigendum to this article was published on 24 October 2007

Abstract

Human T-cell leukemia is a malignant disease that needs various regimens of cytotoxic chemotherapy to overcome drug resistance. Recently, Na+,K+-ATPase has emerged as a potential target for cancer therapy. However, its exact signaling pathway in human T-cell leukemia cell death has not been well defined. In the current study, we found CD95(APO-1) was able to trigger the internalization of plasma membrane Na+,K+-ATPase in Jurkat cells or primary T cells as a mechanism to suppress its activity. This internalization was closely relevant to intracellular glutathione (GSH) depletion in Jurkat cells downstream of Fas-associated death domain protein (FADD) and caspase 8. GSH depletion in Fas L-treated Jurkat cells induced the generation of hydrogen peroxide (H2O2), which subsequently increased the serine phosphorylation of Na+,K+-ATPase α1 subunit. Exogenous H2O2 even mimicked the effect of Fas L to upregulate the serine phosphorylation of Na+,K+-ATPase α1 subunit and suppress Na+,K+-ATPase activity. Overall, our results indicate that CD95(APO-1) induces the FADD- and caspase 8-dependent internalization of Na+,K+-ATPase through intracellular GSH loss, and the subsequent generation of H2O2-mediated serine phosphorylation of Na+,K+-ATPase α1 subunit. Taken together, this study presents a novel regulatory mechanism of Na+,K+-ATPase in CD95(APO-1)-mediated human T-leukemia cell apoptosis.

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Acknowledgements

We thank Professor Cohen and Dr Harper from UK for the generous gifts of FADD-, caspase 8-deficient Jurkat cell, and Dr Bortner CD from USA for providing protocol and comments in measuring plasma membrane depolarization. This project was supported by Natural Science Fund of China to Dr Zi-Chun Hua (30425009, 30330530) and to Dr Yin Wu (30470644, 30600502), and the Ministry of Education of China (TRAPOY 199028418, SRFDP 20030284040).

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Authors and Affiliations

  1. The State Key Lab of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, Nanjing, People's Republic of China

    W Yin, W Cheng, L Shu, J Zhao, J Zhang & Z-C Hua

  2. Pulmonary Critical Care Medicine Branch, National Institute of Health, Bethesda, MD, USA

    W Shen

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Correspondence to Z-C Hua.

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Yin, W., Cheng, W., Shen, W. et al. Impairment of Na+,K+-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide. Leukemia 21, 1669–1678 (2007). https://doi.org/10.1038/sj.leu.2404791

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